Anticancer activity and ADMET properties of resorcinol-bearing lead compounds

Abstract

Heat-shock protein 90 (Hsp90) constitutes about 1-2% of total cellular proteins and is usually present in the cell as a dimer. Hsp90 is a promising anticancer drug target, as cancerous cells are more susceptible to Hsp90 inhibition than normal cells. A large number of different Hsp90 inhibitors have been synthesized to date, but only several of them made to clinical trials. Therefore, there is a great need for new potent Hsp90 inhibitors with improved activity, selectivity, solubility, reduced toxicity and side-effects, as well reduced cost of synthesis. A group of compounds similar to the diarylpyrazole resorcinol class of inhibitors was chemically synthesized. The structure-activity relationship of the compounds was determined in vitro and cell biology methods. Compound binding to Hsp90 was measured by isothermal titration calorimetry (ITC) and the thermal shift assay (TSA). Growth inhibition was determined for two cancer cell lines: cervical cancer (HeLa) and osteosarcoma (U2OS). Main pharmacokinetic and toxicological parameters were estimated in silico by using ADME/Tox Boxes software. Toxicity was determined on mice by method of fixed doses. [...].